Cynthia Peterson
Keywords:
Blood coagulation, heparin, serine protease inhibitors (serpins), fibrinolysis, extracellular matrix
Research Area:
The study of regulatory proteins within the human circulatory system that control a variety of processes, including formation/lysis of blood clots and aspects of humoral immunity and wound healing.
Description of Research:
Within the circulation, sophisticated networks of interactions between proteins and other macromolecules are important for maintaining stasis. Humoral defense mechanisms such as coagulation, fibrinolysis and complement-dependent components of cellular immunity are achieved by interactions of circulatory components with cell surfaces and extracellular matrix or basement membrane regions. Vitronectin, a protein that is found both in the circulation and in the extracellular matrix, interacts with a wide array of ligands that are involved in control of diverse processes including coagulation, fibrinolysis, tumor metastasis, the humoral immune response and cellular migration. Vitronectin binds to other macromolecules and participates in regulatory circuits to control these processes. Some target macromolecules that interact with vitronectin are heparin, PAI-1, proteases such as thrombin and urokinase-type plasminogen activator (uPA), serine protease inhibitor-protease complexes, the uPA receptor, and a sub-class of integrin receptors on the surface of cells. From this extensive list of interactions, several roles for vitronectin are proposed. For example: 1. it provides an adhesive function for interactions of cells with the matrix; 2. it serves in a pro-coagulant role by binding to heparin-like molecules on the vasculature and neutralizing their anticoagulant function; and 3. it controls the process of fibrinolysis or matrix degradation by maintaining protease inhibitor molecules in an active conformation or modulating interactions of cells with integrins and other receptors. Clearly, vitronectin plays diverse roles in the body.
The factors that control the binding interactions and determine activities of vitronectin in the circulation as well as in the matrix are important unsolved issues. We set forth the following as our working hypotheses regarding vitronectin complexes and their activities: 1. Complexes of vitronectin with biological targets (plasminogen activator inhibitor type 1 (PAI-1) or the antithrombin-thrombin pair) associate into higher order structures to give a "clustering" of ligand-binding sites. 2. Vitronectin complexes associate with the matrix and are recognized by cell-surface receptors, with a preference for higher order complexes over free, monomeric vitronectin. 3. Vitronectin is a multi-domain protein with distributed binding sites to control the dynamic processes of coagulation vs. fibrinolysis and binding vs. release from the matrix. To test these hypotheses, a broad spectrum of experimental approaches from molecular biology to biophysics are used.
Contact Information
Cynthia Peterson
Structural and Nanoscale Biophysics
Director, School of Genome Science and Technology
UT
M407 Walters Life Sciences
1414 W. Cumberland Ave.
Knoxville, TN 37996
Email: cbpeters@utk.edu
Degrees
Ph.D. University of Tennessee